Peripheral neuropathy, characterized by slow nerve conduction and by pain, numbness, and tingling in the extremities, can be extremely debilitating. Pain is a serious symptom for many patients, and may be described as a dull aching sensation, an intense burning sensation, or as intermittent, stabbing pain. On occasion, patients notice that their skin is hypersensitive to tactile sensation, such as from standing on their feet or from the touch of clothing or bedding. Some patients note an exaggerated pain resulting from stimulus to the affected area, a form of pain termed allodynia.
Peripheral neuropathy encompasses a wide spectrum of clinical disorders that affect sensory, motor, and autonomic peripheral nerve fibers. Nerve fiber dysfunction can be the result of genetics, systemic or infectious disease, environmental toxins, alcoholism, nutritional deficiencies, or the side effect of certain medications. Peripheral neuropathy can also be caused by traumatic injury, surgery, radiation, and chemotherapy.
Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes, affecting about half of all people with diabetes at some point in their life. The cause of DPN is still under debate, and this lack of knowledge prevents the development of mechanism specific therapies. DPN can also manifest in pre-diabetic individuals with abnormal glucose tolerance. It is known that nerve fiber regeneration is impaired in diabetic nerve, and contributes to the relentless nerve fiber loss characterizing this disorder.
The symptoms of diabetic peripheral neuropathy may include pain, loss of sensory perception, weakness, unsteadiness, and ataxia. Constant pain, which affects 16-26% of people with diabetes, can lead to other health issues such as fatigue, depression, insomnia, and anxiety. Further, lack of protective sensation of the feet puts patients with DPN at high risk for foot ulcerations and non-traumatic amputations resulting from undetected injury.
Pharmacologic management of DPN includes two approaches: (1) treatments that slow the progression of neuropathy and (2) treatments that provide symptom relief. No treatments have yet been identified that can reverse nerve cell damage or loss. The optimization of glycemic control through diet and pharmacotherapy can delay the progression of diabetic neuropathy. Other lifestyle modifications include exercise, weight reduction, smoking cessation, and avoidance of excess alcohol consumption. Neuropathic pain typically does not respond to simple analgesics, and its potential chronicity precludes narcotic therapy as a first choice because of issues associated with tolerance and addiction. Drug therapy for symptomatic relief in DPN includes the use of tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, N-methyl-D-aspartate (NMDA) antagonists, anticonvulsants, and opioids. Unfortunately, there is no evidence that any of these agents modifies the underlying pathophysiology of DPN.
To date, three oral medications have been approved by the U.S. Food and Drug Administration (FDA) for treatment of DPN pain. Pregabalin (Lyrica®, commercially available from Pfizer, New York, N.Y.) is an anticonvulsant agent that binds with high affinity to the α2-δ subunit of calcium channels. This is thought to produce an analgesic effect by decreasing Ca+2 influx into nerve terminals and decreases neurotransmitter release. Side effects of pregabalin include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and attention deficit. A further side effect associated with Lyrica® is an increased risk of suicidal thoughts and behavior.
Duloxetine (Cymbalta®, commercially available from Eli Lilly, Indianapolis, Ind.) is an antidepressant that inhibits serotonin and norepinephrine reuptake. Its mechanism of action involves an increased availability of 5-hydroxytryptamine and noradrenaline, which suppress pain impulses. Side effects of duloxetine include headache, fatigue, nauseas, constipation, and increased blood pressure. This drug cannot be used to treat patients with liver disease, renal failure, or glaucoma.
Tramadol (Nucynta®, commercially available from Johnson & Johnson, New Brunswick, N.J.) is a μ-opioid agonist that also inhibits reuptake of serotonin. Adverse effects include respiratory depression, nausea, somnolence, vomiting, and headache. Patients receiving tramadol require careful monitoring for signs of abuse and addiction. Risk for addiction occurs even under appropriate medical use, and is increased for patients with a family history of substance abuse (including alcohol or drugs) or mental illness (e.g. major depression).
Several topical agents (creams, gels, solutions, sprays, ointments, and patches) have been utilized for the relief of peripheral neuropathic pain including capsaicin, isosorbide dinitrate, nitroglycerin, and lidocaine. Most provide only temporary relief to subjects suffering from neuropathic pain. At present, none of these treatments has demonstrated sufficient efficacy in controlled clinical trials to warrant approval for the treatment of neuropathic pain by the FDA. For example, U.S. Pat. No. 6,143,278 is directed to methods and pharmaceutical compositions for the topical administration of opioid analgesic drugs without substantial transdermal or transmucosal migration of opioid agent into the systemic circulation. However, patients suffering from DPN experienced no pain relief when treated with topical morphine in a KY gel non-occlusive vehicle. U.S. Pat. No. 8,137,711 discloses a topical composition for the treatment of neuropathic pain comprising three active ingredients (ketamine, gabapentin, and clonidine) within a transdermal base reported to synergistically or comprehensively affect multiple pathways and provide a “synergistic shotgun effect.” Side effects are possible, especially dizziness or drowsiness. Manifestation of side effects is a limiting factor for dosing and frequency of application of the topical composition, as well as the site of application and the time of application.
Non-pharmacological treatments of peripheral neuropathy are often categorized as alternative therapies (Head, K., Alternative Medicine Review, 2006, 11(4): 294-329, “Peripheral Neuropathy: Pathogenic Mechanisms and Alternative Therapies”). These treatments include the use of acupuncture, magnet therapy, yoga, mineral supplements (zinc, magnesium, chromium), and various nutrient/botanical therapies (alpha-lipoic acid, acetyl-L-carnitine, thiamine/benfotiamine, methylcobalamin, vitamin E, glutathione, folate, pyridoxine, biotin, myoinositol, omega-3- and omega-6-fatty acids, L-arginine, L-glutamine, taurine, N-acetylcysteine, and St. John's wort). Alternative therapies are typically without side effect and address nutrient deficiencies, oxidative stress, and other etiological factors associated with the development of peripheral neuropathy.
Benfotiamine, a synthetic S-acyl derivative of thiamine, has been reported to prevent the progression of many serious complications of prolonged hyperglycemia, and to have therapeutic applications in diabetic patients. The effects attributed to benfotiamine were extrapolated from in vitro and animal studies (Balakumar, P. et al., The multifaceted therapeutic potential of benfotiamine, PHARMACOLOGICAL RESEARCH, 2010, 61: 482-488). However, the results of a recent clinical trial. concluded that high-dose benfotiamine (300 mg/day) oral supplementation over 24 months has no significant effects upon peripheral nerve function or soluble markers of inflammation in patients with type 1 diabetes, and a trend toward deterioration (Fraser, D. A. et al., The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial, DIABETES CARE, 2012, 35(5):1095-1097).
Various combinations of B vitamins have also been evaluated for the oral treatment of DPN. Metanx®, for example, is a prescription medical food for the dietary management of endothelial dysfunction in patients with diabetic peripheral neuropathy. Metanx® oral tablets comprise the active ingredients calcium L-methylfolate (LMF), pyridoxal-5′-phosphate, and methylcobalamin. Recent clinical trials support the use of Metanx® as a safe approach for short-term alleviation of symptoms associated with diabetic peripheral neuropathy. However, its impact on long-term outcomes is not known (Fonseca, Vivian A. et al., Metanx in Type 2 Diabetes with Peripheral Neuropathy: A Randomized Trial, A MED J, 2013, 126(2): 141-149).
While conventional medicine can offer some relief from neuropathic pain, the potential side effects or addictive nature of many of the medications render long-term use undesirable. Further, pain medications primarily mask symptoms and do not address the underlying pathologies.